Organic anion transporting peptide-based cancer imaging and therapy

Abstract

A dye-drug conjugate for preventing, treating, or imaging cancer having the following structure:wherein R1 and R2 are independently selected from the group consisting of —H, alkyl, alkyl-sulphonate, alkylcarboxylic, alkylamino, aryl, —SO3H, —PO3H, —OH, —NH2, and -halogen; wherein Y1 and Y2 is independently selected from the group consisting of alkyl, aryl, aralkyl, alkylsulphonate, alkylcarboxylic, alkylamino, ω-alkylaminium, ω-alkynyl, PEGyl, PEGylcarboxylate, ω-PEGylaminium, ω-acyl-NH, ω-acyl-lysinyl-, ω-acyl-triazole, ω-PEGylcarboxyl-NH—, ω-PEGylcarboxyl-lysinyl, and ω-PEGylcarboxyl-triazole; wherein X is selected from the group consisting of a hydrogen, halogen, CN, Me, NH2, SH and OH; and R3 and R4 are independently a hydrogen, a therapeutic agent, or an imaging moiety, wherein the therapeutic agent is selected from the group consisting of a platinum-based therapeutic agent, a small molecule therapeutic agent, a peptide, a protein, a polymer, an siRNA, a microRNA, and a nanoparticle, wherein the imaging is a radio-isotope selected from the group consisting of F18, I-125, I-124 I-123, I-131, and small molecule labeled with any of these isotopes, or wherein the imaging moiety is a chelator-complexed radioactive isotope, wherein the radioactive isotope is selected from the group consisting of Cu-64, In-111, Tc-99m, Ga-68, Lu-177, Zo-89, Th-227 and Gd-157.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a national stage application of, and claims the benefit to, PCT Application No. PCT / US2015 / 067393 filed Dec. 22, 2015, which claims priority to U.S. Patent Application Ser. No. 62 / 095,713, filed Dec. 22, 2014, the entire disclosures of which are incorporated herein by reference.TECHNICAL FIELD OF THE INVENTION[0002]A dye-drug conjugate for preventing, treating, or imaging cancer having the following structure:[0003]wherein R1 and R2 are independently selected from the group consisting of —H, alkyl, alkyl-sulphonate, alkylcarboxylic, alkylamino, aryl, —SO3H, —PO3H, —OH, —NH2, and -halogen; wherein Y1 and Y2 is independently selected from the group consisting of alkyl, aryl, aralkyl, alkylsulphonate, alkylcarboxylic, alkylamino, ω-alkylaminium, ω-alkynyl, PEGyl, PEGylcarboxylate, ω-PEGylaminium, ω-acyl-NH, ω-acyl-lysinyl-, ω-acyl-triazole, ω-PEGylcarboxyl-NH—, ω-PEGylcarboxyl-lysinyl, and ω-PEGylcarboxyl-triazole;...

AI Technical Summary

Benefits of technology

[0008]The current invention is based upon the ability of NIR dye-drug conjugates to be taken up and retained by cancer cells, but not by normal cells, with this action being mediated by OATPs. The chemical entities of the NIR dye-drug conjugates comprise three parts: 1) The NIR dye as a targeting ligand for entering cancer cells through their upregulated OATPs. This targeting ligand (NIR dye) can be imaged by fluorescence, as well as by PET (positron emission tomography) or SPECT (single photon emission computed tomography) after further conjugating the targeting ligand with radionuclides, such as Cu-64, Ga-68, F-18, Tc-99, Lu-177, Zo-89, Th-227 and Gd-157; 2) Therapeutic agents that potentially exhibit self-limiting toxicity, such as gemcitabine and cisplatin; and, 3) A linker connecting the targeting ligand to the therapeutic agents for efficient delivery and / or effective release of therapeutic agents once in the cancer cells.

[0009]The present inventor found that NIR dye-drug conjugates can cross cancer cell membranes, blood-brain barrier, bone marrow space, and metastatic solid tumors residing in multiple secondary organ sites resulting from metastasis (such as the lung, the liver, the kidney, the lymph nodes, the brain, the bone, the gastric and digestive system, the intraperitoneal space) and primary tumors residing in the primary organs (such as in the prostate, the lung, the breast, the liver, the colon, the kidney, the bladder, the pancreas, the testes, the ovaries, the brain, the bone marrow, the blood and the digestive system). Due to significant higher levels of NIR dye-drug conjugate uptakes and retentions in cancer cells, as compared with normal cells, embodiments of the invention show the effectiveness of NIR dye-drug conjugates as dual cancer imaging and therapeutic agents for the treatments and diagnosis of human prostate, pancreatic, and brain tumors in mice.

[0010]Embodiments of the invention relate to three aspects. First, the inventor identified important structural features of NIR dye-drug conjugates for efficient uptake and retention by cancer cells. By attaching chemical conjugates at different positions of the NIR dyes, the inventor discovered the most favorable position where chemical conjugation is less likely to affect the specificity of transport of the NIR dye-drug conjugates into cancer cells, relative to the normal cells. Second, the inventor selected two commonly used drugs that are known for their self-limiting toxicity, i.e., gemcitabine and cisplatin, to demonstrate the efficacies of chemotherapy using chemical conjugations. This significantly reduced the toxicity of these drugs in mice, increased the effective transport of these drugs into cancer cells mediated by OATPs, and reduced the doses of the drugs yet achieving the same therapeutic effectiveness against the growth of solid tumors. Third, the inventor demonstrated the effectiveness of these NIR dye-drug conjugates in the most deadly human tumors known to cause significant mortality and morbidity in men and currently there is no effectiveness therapy, namely, human prostate and pancreatic cancers, and brain tumors.

Problems solved by technology

Third, the inventor demonstrated the effectiveness of these NIR dye-drug conjugates in the most deadly human tumors known to cause significant mortality and morbidity in men and currently there is no effectiveness therapy, namely, human prostate and pancreatic cancers, and brain tumors.

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